Behavioural Sensitisation During Dopamine Replacement Therapy in Parkinsons Disease is Reminiscent of the Addicted Brain

F.      Biagioni; A.      Pellegrini; S.      Ruggieri; L.      Murri; A.      Paparelli; F.      Fornai1

doi:10.2174/156802609789378245

Abstract

The intermittent oral intake of the dopamine (DA) precursor L-3,4-dihydroxyphenylalanine (L-DOPA) is the classic therapy of Parkinsons disease (PD). In this way, the drug precursor can be metabolised into the active neurotransmitter DA. Although this occurs throughout the brain, the therapeutic relief is believed to be due to restoring extracellular DA levels within the dorsal striatum (more in the putamen than the caudate nucleus) which lacks endogenous DA as a consequence of the disease process. However, differing from physiological DA transmission, this therapeutic pattern leads to abnormal peaks of non-synaptic DA, which are supposed to trigger behavioural sensitisation expressed as abnormal involuntary movements. A similar pattern of abnormal DA stimulation occurs during methamphetamine (METH) intake. In the present review we will provide evidence showing the similarities between METH- and L-DOPAinduced DA stimulation with an intact and denervated striatum respectively. This comparison will encompass various features; the timing, the areas and the amount of extracellular DA levels which reveal surprising homologies. Such an overlapping between L-DOPA in PD and METH will be further analysed to critically assess the commonalities concerning the following points: abnormal receptor stimulation, recruitment of altered transduction pathways, abnormal gene expression, alterations in the phenotype of striatal neurons, and the establishment of behavioural sensitisation which appear as distinct phenomena (i.e. abnormal involuntary movements in PD and drug addiction in METH abuse); nonetheless, this may also lead to common behavioural alterations (METH-like addictive behaviours in PD patients during the course of DA replacement therapy in subsets of PD patients).

Keywords: L-DOPA, Parkinson's disease, Methamphetamine, Dopamine, Behavioural sensitisation, Dyskinesia, Addiction, Delta fosB